PROJECT SUMMARY The goal of the proposed research career development program is to allow the applicant to acquire training in a new form of brain stimulation using ultrasonic waves. The career development activities will be carried out in a prominent ultrasound laboratory, where the candidate will receive hands-on training in the application and analysis of ultrasonic stimulation in animal models. These activities are intended to aid the applicant in attaining his career goal of becoming a leading investigator of non-invasive modulation of human brain circuits. A major goal of the BRAIN Initiative is the development of tools for manipulating the activity of neural circuits, and in particular those of the human brain. Present-day electromagnetic techniques are limited in focality and ability to target deep structures. Due to its exquisite spatial resolution and ability to be focused through the human skull, stimulation with ultrasonic waves can, in principle, overcome these limitations. Seminal studies have shown that transcranial ultrasound stimulation (TUS) is capable of selectively evoking motor behaviors and recruiting neuronal firing in subcortical regions. However, little is known about how ultrasound interacts with ongoing temporal activity patterns in the brain. In particular, neural oscillations are recognized as fundamental to the brain's information processing, and aberrant rhythms have been implicated in various neurological and psychiatric disorders. It is thus important to determine whether TUS may be used to modify neural oscillations. The long-term goal of this research program is to allow for systematic control of targeted spatiotemporal activity patterns in the human brain. The objective of the proposed research project is to evaluate the safety and efficacy of a new form of TUS, here termed ?repetitive TUS? (rTUS), that delivers the ultrasound in a periodic and sustained fashion. The central hypothesis of the research is that by controlling the timing of the TUS stimuli, one can modulate frequency-specific brain rhythms. This hypothesis will be tested by conducting in vivo physiological measurements in anesthetized mice. The specific aims of the research are: (1) to determine the safety limits of the technique in terms of intensity and duration by monitoring brain temperature during rTUS, and (2) to measure the effects of rTUS on the amplitude and phase of both low- and high- frequency rhythms in multiple brain regions. The findings of this research may lead to a novel technique for interrogating the functional role of neural oscillations. Moreover, the proposed technique may achieve cell specificity by preferentially stimulating those neurons firing at the targeted frequency.